Advanced Pharmacokinetics

Question 1

Phase I metabolism

Answer 1

creates a chemical functional group on a drug

(eg many Cyt-p450 reactions)

Question 2

Phase II metabolism

Answer 2

conugation of a water soluble molecule to a functional group on a drug

(makes drug more water soluble and/or inactive)

Question 3

Most drugs distribute

Answer 3

rapidly; reach a distribution equilibrium, behave as if in a single compartment

Question 4

Rate of drug elimination is proportional to

Answer 4

concentration in plasma (first-order kinetics)

Question 5

Drugs given by rapid IV administration disribute and are eliminated by

Answer 5

rapidly; first-order kinetics (proportional to concentration in plasma)

Question 6

In short-term IV infusion, drug is administered

Answer 6

at a constant rate

Question 7

In short-term IV infusion, drug is distributed and eliminated

Answer 7

rapidly; first-order

Question 8

How does drug concentration rise in rapid-IV?

Answer 8

rapidly, administered all at once

Question 9

How does drug concentration increase in short-term IV?

Answer 9

• does not rise constantly
  
  • as concentration increases, rate of elimination increases
  • tf as it accumulates, it accumulates slower and slower because elimination is increasing
  • concentration rises, then plateaus

Question 10

What happens to drug concentration when short-term IV infusion is stopped?

Answer 10

eliminated exponentially (as if it had been a bolus/rapid-IV administration)

Question 11

What is the difference in peak concentration between rapid and short-term IV?

Answer 11

peak is much higher in rapid bc administered all at once; short-term is infused gradually, tf peak concentration will never be as high as rapid IV

Question 12

What feature of drug concentration differentiates short and long term IV infusion?

Answer 12

long term IV infusion reaches a steady state drug concentration; short term IV infusion does not

Question 13

The steady-state concentration of drug in long term IV infusion is proportional to

Answer 13

• the infustion rate
  
  • rate of infusion = rate of elimination
• tf easy to ‘dial up’ a particular concentration in a patient by changing the rate of infusion:
  
  • infusion rate = Css
  • 2x infusion rate = 2x Css
  • 0.5x infusion rate = 0.5x Css

Question 14

How are multiple dosing and long term IV administrations related?

Answer 14

pattern of accumulation in long term IV infusion is the same if the drug is given at a constant rate or in a series of multpile doses; both are a constant rate

Question 15

The dosing interval of most drugs is

Answer 15

half-life

Question 16

What is a loading dose?

Answer 16

volume distribution x concentration

use to establish a steady-state blood concentration before administering multiple doses of a drug (usually with a long half-life)

Question 17

Absorption of orally administered drugs is primarily

Answer 17

lipid diffusion in the small intestine

Question 18

Absorption of orally administered drugs depends on

Answer 18

concentration in the small intestine (greater concentration = greater drive for absorption)

Question 19

Elimiantion rate of orally administered drugs depends on

Answer 19

concentration in the blood (first order elimination)

Question 20

What are the features of oral administration?

Answer 20

• peak concentration is not as high as IV
  
  • some drug is eliminated during absorption
  • not all drug may be absorbed from GI (absorption is not a factor in IV)
  • some may be first-pass metabolised in the liver, reducing concentration in the blood

Question 21

What is bioavailability?

Answer 21

• proportion of active drug that enters the systemic circulation
• (100% with IV, less via other routes)
• affected by:
  
  • how much is absorbed
  • how much of the drug undergoes:
    
    • first pass hepatic metabolism (oral admin)
    • local metabolism (eg in GI prior to absorption, at skin or muscle for intramuscular injection)

Question 22

Bioavailability is calculated by

Answer 22

• area under the concetrantio vs time curves for IV and oral administration:
  
  • (AUC-oral/AUC-IV) X 100%
• if oral bioavalability is less than IV, need to administer more drug to get the same dose:
  
  • IV = 100mg; oral = 75%
  • 100/0.75 = 133mg oral dose

Question 23

What are the factors that complicate drug use?

Answer 23

• unusual drug behaviour
• interpatient variability

Question 24

What are unusual drug behaviours?

Answer 24

• low bioavailability - drug is sensitive to variability
• slow distribution such that some is eliminated during distribution
• sufficiently high concentrations of drug to saturate elimination processes, making elimination rate constant (zero-order kinetics)

Question 25

How does low bioavailability increase sensitivity to variability in concentration?

Answer 25

* 90+/-5%, variation is (95-85)/85 = 12% * 10+/-5%, variation is (15-5)/5 = 200% --\> pt ends up with twice as much drug as another

Question 26

Drugs with low bioavailability need to be administered by

Answer 26

Routes that avoid first-pass metbolism: * skin (patches) * lungs (gas) * nose * rectum * subcutaneous injection *these may have absorption factors that contribute to bioavailability; IV avoids both issues but not always appropriate*

Question 27

What are the consequences of rapid IV administration of a slow-distributing drug?

Answer 27

* rapidly distrubutes in central compartment (blood, heart, brain, liver, tissues) * slowly distributes into peripheral compartment (fat and muscle) * **both compartments comprise the volume distribution** * tf initially have a high concentration in a lower volume * drug is eliminated from central while it distributes to peripheral * reaches EQB * after EQB, only elimination

Question 28

What is the danger of slow-distributing drugs?

Answer 28

* peak concentration is higher than predicted by volume distribution * takes longer to reach the peripheral comparments and therefore is concentrated in the central compartment * if the drug has a narrow therapeutic index, this concentration can easily be in the toxic range

Question 29

What is the consequence of zero order elimination (enzymes are saturated)?

Answer 29

* in single dosing, get constant elimination while the system is saturated and exponential elimination when concentration falls * in multpile dosing, zero order elimination prohibits reaching a steady state * increasing concentration doesn't increase elimination * tf concentration of drug continues to rise * in practice, other enzyme systems take over = pseudo SS

Question 30

What causes interpatient variability?

Answer 30

* age * genetic factors * idiosyncratic reactions * disease * drug-drug interactions

Question 31

How does age affect drug concentration?

Answer 31

reduced excretion and metabolism at extremes of age increases the half-life and persistence of some drugs - tf may need lower doses if multi-dosing

Question 32

Babies are deficient in

Answer 32

drug metabolizing enzymes, particularly phase II conjugation ## Footnote **tf increased plasma half life of drugs**

Question 33

Elderly are deficient in

Answer 33

Cyt-p450 enzymes ## Footnote **increases half-life of drugs**

Question 34

What genetic factors contribute to drug metabolism?

Answer 34

* polymorphisms of enzymes (fast or slow) * ethnic expression eg ALDH in Chinese

Question 35

In a pharmacodynamic drug-drug interaction

Answer 35

drug A modifies the effect of drug B **without affecting its concentration**

Question 36

In a pharmacokinetc drug-drug interaction

Answer 36

drug A **modifies the concentration** of drug B at its receptor

Question 37

To be clinically significant, drug-drug interactions require

Answer 37

* the drug affected to have a narrow tehrapeutic index * its concentration-response curve is steep such that small changes in concentration have large changes in effect

Question 38

Pharmacodynamic interactions can occur at

Answer 38

receptors eg antagonism; can cause physiological effects

Question 39

Pharmacokinetic interactions act at the level of

Answer 39

* absorption * distribution * metabolism * excretion

Question 40

Pharmacokinetic interactions at the level of absorption

Answer 40

* alter gastric emptying rates * decreased by opiates * increased my metaclopramide * formation of poorly-absorbed complexes * calcium & tetracyclines

Question 41

Pharmacokinetic interactions at the level of distribution

Answer 41

* displacement from plasma protein binding sites transiently increases [unbound drug] * causes an increase in elimination that corrects [unbound drug] * overall decrease in drug, but no change in 'free drug' in plasma * eg aspirin displacing phenytoin

Question 42

Pharmacokinetic interactions at the level of metabolism

Answer 42

* induction of p450 (rifampicin, ethanol) decreases half-life/concentration in plasma, and * eg warfarin * leads to increased bioactivation that can increase toxicity * eg paracetamol * inhibition of p450 (steroids, cimetidine) increases half-life/increases plasma concentration * eg phenytoin, digoxin

Question 43

Pharmacokinetic interactions at the level of excretion

Answer 43

* alter protein binding, affecting filtration * alter tubular secretion (eg blocking it with probenic acid for masking) * alter urine flow and pH (eg using bicarb to alkalize urine to tx aspirin overdose)